Antidepressants are insurmountable inhibitors of the human serotonin transporter

The vast majority of clinically active antidepressants are selective serotonin reuptake inhibitors (SSRIs). Although SSRIs have been used in the clinic for decades, little is known about how these molecules interact with SERT. It has been proposed that tricyclic antidepressants such as imipramine bind to a site distinct from that of other antidepressants and that S‐citalopram binds to a high affinity site allosterically modulated by serotonin. However, most antidepressants (tricyclics including imipramine, SSRIs or serotonin norepinephrine reuptake inhibitors (SNRIs)) have been reported to be competitive with serotonin. Therefore, there is no real consensus about whether antidepressants are competitive or non‐competitive with serotonin. In contrast, cocaine has consistently been reported as competitive in nature at the 3 monoamine transporters. Using uptake saturation experiments in recombinant cell lines expressing the human SERT, we show that several classes of antidepressants (tricyclics, SSRIs and SNRIs) affect serotonin transport by decreasing the Vmax without affecting the Km, appearing insurmountable by serotonin. In contrast, cocaine increased the Km with little effect on the Vmax, appearing surmountable by serotonin. In conclusion, our data suggest that cocaine is a competitive SERT inhibitor whereas all tested antidepressants appear insurmountable in functional uptake assays.